CZ351297A3 - Transdermal therapeutic system for testosterone administration - Google Patents
Transdermal therapeutic system for testosterone administration Download PDFInfo
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- CZ351297A3 CZ351297A3 CZ973512A CZ351297A CZ351297A3 CZ 351297 A3 CZ351297 A3 CZ 351297A3 CZ 973512 A CZ973512 A CZ 973512A CZ 351297 A CZ351297 A CZ 351297A CZ 351297 A3 CZ351297 A3 CZ 351297A3
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- Prior art keywords
- active ingredient
- testosterone
- carrier
- adhesive
- adhesive layer
- Prior art date
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- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 title claims abstract description 31
- 229960003604 testosterone Drugs 0.000 title claims abstract description 17
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 16
- 150000003515 testosterones Chemical class 0.000 claims abstract description 7
- 239000013543 active substance Substances 0.000 claims abstract description 4
- 239000004480 active ingredient Substances 0.000 claims description 40
- 239000000853 adhesive Substances 0.000 claims description 25
- 230000001070 adhesive effect Effects 0.000 claims description 21
- 239000012528 membrane Substances 0.000 claims description 17
- -1 testosterone ester Chemical class 0.000 claims description 17
- 239000012790 adhesive layer Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000010408 film Substances 0.000 claims description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- 229920001296 polysiloxane Polymers 0.000 claims description 9
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 6
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 6
- 229920000858 Cyclodextrin Polymers 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 239000013039 cover film Substances 0.000 claims description 4
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 claims description 3
- 229940087168 alpha tocopherol Drugs 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000011888 foil Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000003961 penetration enhancing agent Substances 0.000 claims description 3
- 229960003484 testosterone enanthate Drugs 0.000 claims description 3
- VOCBWIIFXDYGNZ-IXKNJLPQSA-N testosterone enanthate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 VOCBWIIFXDYGNZ-IXKNJLPQSA-N 0.000 claims description 3
- 229960001712 testosterone propionate Drugs 0.000 claims description 3
- 229960000746 testosterone undecanoate Drugs 0.000 claims description 3
- UDSFVOAUHKGBEK-CNQKSJKFSA-N testosterone undecanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCCCCCC)[C@@]1(C)CC2 UDSFVOAUHKGBEK-CNQKSJKFSA-N 0.000 claims description 3
- 229960000984 tocofersolan Drugs 0.000 claims description 3
- 239000002076 α-tocopherol Substances 0.000 claims description 3
- 235000004835 α-tocopherol Nutrition 0.000 claims description 3
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 claims description 2
- 239000001116 FEMA 4028 Substances 0.000 claims description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 2
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 claims description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 2
- 229960004853 betadex Drugs 0.000 claims description 2
- 229960001566 methyltestosterone Drugs 0.000 claims description 2
- 229920002635 polyurethane Polymers 0.000 claims description 2
- 239000004814 polyurethane Substances 0.000 claims description 2
- 229920001289 polyvinyl ether Polymers 0.000 claims description 2
- HPFVBGJFAYZEBE-ZLQWOROUSA-N testosterone cypionate Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(CCC(=O)C=C4CC3)C)CC[C@@]21C)C(=O)CCC1CCCC1 HPFVBGJFAYZEBE-ZLQWOROUSA-N 0.000 claims description 2
- 239000000178 monomer Substances 0.000 description 9
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 6
- 239000003623 enhancer Substances 0.000 description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 4
- FWLDHHJLVGRRHD-UHFFFAOYSA-N decyl prop-2-enoate Chemical compound CCCCCCCCCCOC(=O)C=C FWLDHHJLVGRRHD-UHFFFAOYSA-N 0.000 description 4
- 229920000058 polyacrylate Polymers 0.000 description 4
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 3
- 125000005250 alkyl acrylate group Chemical group 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000013464 silicone adhesive Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 238000000576 coating method Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
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- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
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- 230000001105 regulatory effect Effects 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000003466 welding Methods 0.000 description 2
- JKNCOURZONDCGV-UHFFFAOYSA-N 2-(dimethylamino)ethyl 2-methylprop-2-enoate Chemical compound CN(C)CCOC(=O)C(C)=C JKNCOURZONDCGV-UHFFFAOYSA-N 0.000 description 1
- DPBJAVGHACCNRL-UHFFFAOYSA-N 2-(dimethylamino)ethyl prop-2-enoate Chemical compound CN(C)CCOC(=O)C=C DPBJAVGHACCNRL-UHFFFAOYSA-N 0.000 description 1
- BEWCNXNIQCLWHP-UHFFFAOYSA-N 2-(tert-butylamino)ethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCNC(C)(C)C BEWCNXNIQCLWHP-UHFFFAOYSA-N 0.000 description 1
- KDAKDBASXBEFFK-UHFFFAOYSA-N 2-(tert-butylamino)ethyl prop-2-enoate Chemical compound CC(C)(C)NCCOC(=O)C=C KDAKDBASXBEFFK-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- WDQMWEYDKDCEHT-UHFFFAOYSA-N 2-ethylhexyl 2-methylprop-2-enoate Chemical compound CCCCC(CC)COC(=O)C(C)=C WDQMWEYDKDCEHT-UHFFFAOYSA-N 0.000 description 1
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 description 1
- YXYJVFYWCLAXHO-UHFFFAOYSA-N 2-methoxyethyl 2-methylprop-2-enoate Chemical compound COCCOC(=O)C(C)=C YXYJVFYWCLAXHO-UHFFFAOYSA-N 0.000 description 1
- HFCUBKYHMMPGBY-UHFFFAOYSA-N 2-methoxyethyl prop-2-enoate Chemical compound COCCOC(=O)C=C HFCUBKYHMMPGBY-UHFFFAOYSA-N 0.000 description 1
- QZPSOSOOLFHYRR-UHFFFAOYSA-N 3-hydroxypropyl prop-2-enoate Chemical compound OCCCOC(=O)C=C QZPSOSOOLFHYRR-UHFFFAOYSA-N 0.000 description 1
- WHNPOQXWAMXPTA-UHFFFAOYSA-N 3-methylbut-2-enamide Chemical compound CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 description 1
- NQSLZEHVGKWKAY-UHFFFAOYSA-N 6-methylheptyl 2-methylprop-2-enoate Chemical compound CC(C)CCCCCOC(=O)C(C)=C NQSLZEHVGKWKAY-UHFFFAOYSA-N 0.000 description 1
- DXPPIEDUBFUSEZ-UHFFFAOYSA-N 6-methylheptyl prop-2-enoate Chemical compound CC(C)CCCCCOC(=O)C=C DXPPIEDUBFUSEZ-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 101100202589 Drosophila melanogaster scrib gene Proteins 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical group [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 206010052649 Primary hypogonadism Diseases 0.000 description 1
- 206010059594 Secondary hypogonadism Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004840 adhesive resin Substances 0.000 description 1
- 229920006223 adhesive resin Polymers 0.000 description 1
- 206010003883 azoospermia Diseases 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- LNCPIMCVTKXXOY-UHFFFAOYSA-N hexyl 2-methylprop-2-enoate Chemical compound CCCCCCOC(=O)C(C)=C LNCPIMCVTKXXOY-UHFFFAOYSA-N 0.000 description 1
- LNMQRPPRQDGUDR-UHFFFAOYSA-N hexyl prop-2-enoate Chemical compound CCCCCCOC(=O)C=C LNMQRPPRQDGUDR-UHFFFAOYSA-N 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 201000003368 hypogonadotropic hypogonadism Diseases 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- PBOSTUDLECTMNL-UHFFFAOYSA-N lauryl acrylate Chemical compound CCCCCCCCCCCCOC(=O)C=C PBOSTUDLECTMNL-UHFFFAOYSA-N 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000008634 oligospermia Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
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- 238000013268 sustained release Methods 0.000 description 1
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- 229920001897 terpolymer Polymers 0.000 description 1
- 150000003772 α-tocopherols Chemical class 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gynecology & Obstetrics (AREA)
- Nanotechnology (AREA)
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- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Description
Oblast technikyTechnical field
Předložený vynález se týká transdermálního terapeutického systému pro podávání testosteronu nebo jeho derivátů jako účinné látky.The present invention relates to a transdermal therapeutic system for administering testosterone or derivatives thereof as an active ingredient.
Dosavadní stav technikyBACKGROUND OF THE INVENTION
Podle současného stavu techniky se testosteron a deriváty testosteronu používají konkrétně pro hormonální náhradní terapii mužů. Dalšími indikacemi, spolu s primárním a sekundárním hypogonadismem, jsou oligozoospermie, impotence a předčasná ejakulace. V současnosti probíhají testy na jejich použití v případě oeteoporozy u mužů; viz například Rapado a kol., in: Trends in Osteoporosis, 1 (1989) 1-9.According to the state of the art, testosterone and testosterone derivatives are used specifically for hormone replacement therapy in men. Other indications, along with primary and secondary hypogonadism, are oligozoospermia, impotence and premature ejaculation. Tests are currently underway for use in men with oeteoporosis; see, for example, Rapado et al., in: Trends in Osteoporosis, 1 (1989) 1-9.
Díky vysokému účinku prvního průchodu je testosteron rozsáhle neúčinný při orální podání. Proto se při náhradní terapii podávají buď orálně účinné estery, jako je undekanoát testosteronu, nebo injekční přípravky s prodlouženým účinkem, jako je enanthát testosteronu a propionát testosteronu.Due to the high first-pass effect, testosterone is largely ineffective when administered orally. Therefore, either orally active esters such as testosterone undecanoate or sustained-release injectables such as testosterone enanthate and testosterone propionate are administered in replacement therapy.
Tato data poskytují řadu výchozích bodů pro smysluplný vývoj transdermálních terapeutických systémů (TTS). S použitím těchto systémů se lze vyhnout vysokým dávkám účinné složky při orální dávkování, obejdou se bolestivé injekce a hladina v krvi může být lépe regulována a lépe přizpůsobena dennímu rytmu.These data provide a number of starting points for meaningful development of transdermal therapeutic systems (TTS). Using these systems, high doses of the active ingredient in oral dosages can be avoided, painful injections can be bypassed, and blood levels can be better regulated and better adapted to daily rhythm.
Například v US-A-4 704 282 se popisuje transdermální terapeutický systém, který má nosnou folii (zpevňující prostředek), zásobník účinné složky a odstranitelnou krycí folii (odlepovací pásek). Zásobník účinné složky může být ve formě vodného nebo nevodného gelu nebo polymerního materiálu, v němž je účinná složka rozpuštěna v koncentraci, která není vyšší, než je nasycená koncentrace účinné složky v materiálu matrice. Matrice může obsahovat prostředky zvyšující prostupnost. Účinnou složkou, která má být podávána, může být například testosteron. Samozřejmě je-li testosteron v transdermálním terapeutickém systému přítomen v méně než nasyceném roztoku, je pro získání vyhovujících hladin v krvi přítomnost prostředků zvyšujících propustnost nezbytná, viz WO-A-9 210 231, str. 11, řádek 33.For example, US-A-4 704 282 discloses a transdermal therapeutic system having a carrier film (a strengthening agent), an active ingredient reservoir, and a removable cover film (a release strip). The reservoir of the active ingredient may be in the form of an aqueous or non-aqueous gel or polymeric material in which the active ingredient is dissolved at a concentration not greater than the saturated concentration of the active ingredient in the matrix material. The matrix may include permeation enhancers. For example, the active ingredient to be administered may be testosterone. Of course, if testosterone is present in a less than saturated solution in the transdermal therapeutic system, the presence of permeation enhancers is necessary to obtain satisfactory blood levels, see WO-A-9 210 231, page 11, line 33.
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V US-A-4 849 224 se navrhuje transdermální terapeutický systém, v němž je zásobník účinné složky tvořen nosnou folií (podkladová folie) a porézní membránou. Účinnou složkou může být testosteron nebo ester testosteronu. Kromě účinné složky mohou být přítomny prostředky zvyšující prostupnost. Na použitelnost tohoto známého systému je však třeba pohlížet kriticky, protože zásobník účinné složky, který je tvořen laminátem z nosné folie a membrány, se lepí na kůži kroužkem lepidla. Jelikož je lepidlo naneseno ve formě prstence, je ve skutečnosti vytvořeno okno, skrz které může účinná složka a prostředek zvyšující prostupnost pronikat do kůže přes membránu bez toho, že by se prostředek zvyšující prostupnost dostal nezbytně do styku s lepidlem, přičemž pro ochranu lepidla jsou vytvořeny přídavné prstencové těsnícími prvky. Jelikož může být s prstencovou lepivou zónou získána pouze omezená lepivost, je velikost této známé náplasti omezena.US-A-4,849,224 proposes a transdermal therapeutic system in which the reservoir of the active ingredient consists of a carrier film (backing film) and a porous membrane. The active ingredient may be testosterone or a testosterone ester. In addition to the active ingredient, permeation enhancers may be present. However, the applicability of this known system should be viewed critically, since the reservoir of the active ingredient, which consists of a carrier film and membrane laminate, is adhered to the skin by an adhesive ring. Since the adhesive is applied in the form of a ring, a window is actually formed through which the active ingredient and the permeation enhancer can penetrate the skin through the membrane without necessarily coming into contact with the glue, and to protect the adhesive are provided additional annular sealing elements. Since only a limited tack can be obtained with the annular adhesive zone, the size of this known patch is limited.
WO-A-9 210 231 = EP-A-0 562 041 je založen na stavu techniky z US-A4 849 224, podle nějž je vytvořen prstenec lepidla pro adhezi transdermálního terapeutického systému ke kůži; viz WO-A-9 210 231, str. 13, řádky 18/19. Alternativně je navržena základní vrstva lepidla pod zásobníkem (zvláštní základní vrstva lepidla ležící pod zásobníkem) a ktomu adhezní povlak pro zásobník (adhezní překrytí zásobníku). Jelikož je však podle tohoto známého stavu techniky pro podávání testosteronu nezbytné použití prostředků zvyšujících prostupnost, není jasné, jak chce WO-A-9 210 231 zabránit nežádoucímu proniknutí prostředku zvyšujícího prostupnost do lepidla, pokud není lepidlo vytvořeno v prstencovité formě.WO-A-9 210 231 = EP-A-0 562 041 is based on the prior art of US-A4 849 224, according to which an adhesive ring is formed for adhering a transdermal therapeutic system to the skin; see WO-A-9 210 231, page 13, lines 18/19. Alternatively, a base layer of adhesive is provided below the container (a separate base layer of adhesive lying beneath the container) and an adhesive coating for the container (adhesive overlap of the container). However, since the use of permeation enhancers is necessary in the prior art for the administration of testosterone, it is not clear how WO-A-9 210 231 intends to prevent undesirable penetration of the permeation enhancers into the adhesive unless the adhesive is formed in an annular form.
WO-A 9 503 764, WO-A-9 423 707 a US-A-5 152 997 také popisují transdermální terapeutické systémy pro podávání testosteronu, přičemž tyto systémy jsou systémy se zásobníky, v nichž je účinná složka přítomna v nižší než nasycené formě, a jsou opatřeny urychlovačem prostupnosti. Tyto popisy známého stavu tak korespondují se stavem techniky, jak je uveden ve WO-A9 210 231, str. 11, řádek 33.WO-A 9 503 764, WO-A-9 423 707 and US-A-5 152 997 also disclose transdermal therapeutic systems for the administration of testosterone, which systems are reservoir systems in which the active ingredient is present in a lower than saturated form , and are provided with a permeability accelerator. Thus, these prior art descriptions correspond to the prior art as disclosed in WO-A9 210 231, page 11, line 33.
Úkolem vynálezu je poskytnout transdermální terapeutický systém pro podávání testosteronu nebo derivátů testosteronu, který nevyžaduje použití prostředků zvyšujících prostupnost a který zaručuje dostatečnou hladinu účinné složky v krvi.SUMMARY OF THE INVENTION It is an object of the present invention to provide a transdermal therapeutic system for the administration of testosterone or testosterone derivatives which does not require the use of permeation enhancers and which provides a sufficient level of the active ingredient in the blood.
Podstata vynálezuSUMMARY OF THE INVENTION
Pro tento účel je navržen podle předloženého vynálezu transdermální terapeutický systém (TTS) pro podávání testosteronu nebo derivátů testosteronu jako účinné složky, který máFor this purpose, a transdermal therapeutic system (TTS) for administering testosterone or testosterone derivatives as an active ingredient having
- nosnou folii (podkladovou folii),- carrier film (backing film),
- zásobník,- container,
- alkoholový nosič účinné složky,- alcohol carrier of the active ingredient,
- adhezní vrstvu pro styk systému s kůží, aan adhesive layer for contacting the system with the skin, and
- odstranitelnou krycí folii (odlepovací pásek), v němž- a removable cover film (release strip) in which:
- systém neobsahuje prostředek zvyšující prostupnost,- the system does not contain a permeation enhancer,
- účinná složka je v nosiči účinné složky přítomna v nasycení athe active ingredient is present in the carrier of the active ingredient in saturation, and
- mezi zásobníkem a adhezní vrstvou je vytvořena membrána,- a membrane is formed between the container and the adhesive layer,
- která neřídí uvolňování účinné složky, zatímco uvolňování účinné složky řídí adhezní vrstva.- which does not control the release of the active ingredient, while the release of the active ingredient controls the adhesive layer.
Vynález je založen na překvapivém zjištění, že dostatečného množství účinné složky v krvi může být dosaženo také či zejména tehdy, když je účinná složka přítomna v nosiči pro účinnou látku v nasycení, zatímco WO-A9 210 231 vyžaduje nižší koncentraci než nasycení účinné složky.The invention is based on the surprising finding that a sufficient amount of the active ingredient in the blood can be achieved also or particularly when the active ingredient is present in the carrier for the active ingredient in saturation, whereas WO-A9 210 231 requires a lower concentration than the saturation of the active ingredient.
Podle vynálezu lze použít jako deriváty testosteronu ester testosteronu, zejména enanthát testosteronu, cipionát testosteronu, propionát testosteronu nebo undekanoát testosteronu, nebo nižší alkyltestosterony, zejména methyltestosteron.According to the invention, testosterone ester, in particular testosterone enanthate, testosterone cipionate, testosterone propionate or testosterone undecanoate, or lower alkylltestosterones, in particular methyltestosterone, can be used as testosterone derivatives.
Účinná složka může být přítomna ve formě komplexu s cyklodextrinem nebo deriváty cyklodextrinu, zejména s β-cyklodextrinem.The active ingredient may be present in the form of a complex with cyclodextrin or cyclodextrin derivatives, in particular β-cyclodextrin.
Membránou může být membrána z polyethylenu nebo membrána z polypropylenu.The membrane may be a polyethylene membrane or a polypropylene membrane.
Podle výhodného provedení je zásobník tvořen nosnou folií a membránou.According to a preferred embodiment, the container is formed by a carrier film and a membrane.
Podle vynálezu může být alkoholovým nosičem účinné látky ethanol nebo nízkomolekulární monohydroxyalkohol, jako je isopropanol, nebo nízkomolekulární polyhydroxyalkohol, například propylenglykol, nebo jejich směs.According to the invention, the alcoholic active ingredient can be ethanol or a low molecular weight monohydroxy alcohol such as isopropanol, or a low molecular weight polyhydroxy alcohol, for example propylene glycol, or a mixture thereof.
• · • · · ·• • •
Pro adhezní vrstvu podle vynálezu může být vybráno lepidlo citlivé na tlak (samolepící lepidlo), odolné vůči alkoholu, na bází například polyurethanu, isobutylenu, polyvinyletheru, silikonu nebo akrylátu.An alcohol-resistant pressure-sensitive adhesive (pressure-sensitive adhesive) based on, for example, polyurethane, isobutylene, polyvinyl ether, silicone or acrylate may be chosen for the adhesive layer according to the invention.
Lepidlem na bázi silikonu může být silikonové lepidlo, které je založeno na dvou hlavních složkách; polymeru nebo lepidlu, zejména polysiloxanu, a lepící pryskyřici. Polysiloxanové lepidlo je obvyklo tvořeno zesíťovadlem lepidla, typicky vysokomolekulárním polydiorganosiloxanem, a pryskyřicí, aby se použitím vhodného organického rozpouštědla získala trojrozměrná křemičitanová struktura. Směs pryskyřice s polymerem je nejdůiežitějším faktorem pro změnu fyzikálních vlastností polysiloxanových lepidel; viz například Sobieski a kol., Silicone Pressure Sensitive Adhesives, Handbook of Pressure Sensitive Adhesive Technology, 2.vyd., str. 508-517 (ed. D. Satas), Van Nostrand Reinhold, New York (1989).The silicone-based adhesive may be a silicone adhesive based on two main components; a polymer or an adhesive, in particular polysiloxane, and an adhesive resin. The polysiloxane adhesive is typically comprised of an adhesive crosslinker, typically a high molecular weight polydiorganosiloxane, and a resin to obtain a three-dimensional silicate structure using a suitable organic solvent. The resin / polymer mixture is the most important factor for altering the physical properties of polysiloxane adhesives; see, for example, Sobieski et al., Silicone Pressure Sensitive Adhesives, Handbook of Pressure Sensitive Adhesive Technology, 2nd Ed., pp. 508-517 (ed. D. Satas), Van Nostrand Reinhold, New York (1989).
Vhodná na samolepící silikonová lepidla lze běžně získat pod ochrannou známkou BIO-PSA X7.Suitable for self-adhesive silicone adhesives are commonly available under the trademark BIO-PSA X7.
Dalším příkladem lepidel citlivých na tlak na bázi silikonů je trimethylovaný silikon-dioxid, který byl zpracován s polydimethylsiloxanem s koncovými trimethylsiloxyskupinami.Another example of silicone-based pressure sensitive adhesives is trimethylated silicone dioxide which has been treated with trimethylsiloxy terminal polydimethylsiloxane.
Lepidlem na bázi akrylátú může být jakýkoliv homopolymer, kopolymer nebo terpolymer, sestávající z různých derivátů kyseliny akrylové.The acrylate-based adhesive may be any homopolymer, copolymer or terpolymer consisting of various acrylic acid derivatives.
Například mohou být akrylátovými polymery polymery jednoho nebo více monomerů kyseliny akrylové a jiných kopolymerovatelných monomerů. Akrylátové polymery také mohou obsahovat kopolymery alkylakrylátú a/nebo methakrylátů a/nebo kopolymerovatelných sekundárních monomerů nebo monomerů s funkčními skupinami. Kohezní vlastnosti získaných akrylátových polymerů je možno měnit změnami množství každého typu, který se přidá jako monomer. Obecně sestává akrylátový polymer z nejméně 50 % hmotn. akrylátového, methakrylátového, alkylakrylátového nebo alkylmethakrylátového monomeru, od 0 do 20 % funkčního monomeru, kopolymerovatelného s akrylátem, a od 0 do 40 % odlišného monomeru.For example, the acrylate polymers may be polymers of one or more acrylic acid monomers and other copolymerizable monomers. The acrylate polymers may also comprise copolymers of alkyl acrylates and / or methacrylates and / or copolymerizable secondary or functionalized monomers. The cohesive properties of the obtained acrylate polymers can be varied by varying the amount of each type that is added as the monomer. Generally, the acrylate polymer consists of at least 50 wt. an acrylate, methacrylate, alkyl acrylate or alkyl methacrylate monomer, from 0 to 20% of a functional monomer copolymerizable with acrylate, and from 0 to 40% of a different monomer.
Akrylátovými monomery, které mohou být použity s kyselinou akrylovou, jsou kyselina methakrylová, butylakrylát, butylmethakrylát, hexylakrylát, hexylmethakrylát, isooktylakrylát, isooktylmethakrylát, 2-ethylhexylakrylát, 2ethylhexylmethakrylát, decylakrylát, decylmethakrylát, dodecylakrylát, dodecylmethakrylát, tridecylakrylát a tridecylmethakrylát.Acrylate monomers which may be used with acrylic acid are methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexylacrylate, 2-ethylhexyl methacrylate, decylacrylate, dodecyl acrylate, decylacrylate, decylacrylate, decylacrylate,
Jako funkční monomery, které jsou kopolymerovatelné s výše uvedenými akryláty, methakryláty, alkylakryláty nebo alkylmethakryláty mohou být například použity kyselina akrylová, kyselina methakrylová, kyselina ♦ ·· ♦ ·· ······ c ··········· J ······· • · · · ······ • · · · · · ······· ······· · · · maleinové, maleinanhydrid, hydroxyethylakrylát, hydroxypropylakrylát, akrylamid, dimethylakrylamid, akrylonitril, dimethylaminoethylakrylát, dimethylaminoethylmethakrylát, terc.butylaminoethylakrylát, terc.butylaminoethylmethakrylát, methoxyethylakrylát a methoxyethylmethakrylát.As the functional monomers which are copolymerizable with the above-mentioned acrylates, methacrylates, alkyl acrylates or alkyl methacrylates, for example, acrylic acid, methacrylic acid, acid may be used c ·· ♦ ·· ······ c ········· J ·················· · · · · · · · · · · · · · Maleic, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate , acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate.
Další podrobnosti a příklady samolepivých akrylátů, vhodných pro vynález, jsou popsány v Satas Handbook of Pressure Sensitive Adhesive Technology Acrylic Adhesives, 2. vyd., str. 396-456 (ed. D. Satas), Vart Nostrand Reinhold, New York (1989).Further details and examples of self-adhesive acrylates suitable for the invention are described in Satas Handbook of Pressure Sensitive Adhesive Technology Acrylic Adhesives, 2nd Ed., Pp. 396-456 (ed. D. Satas), Vart Nostrand Reinhold, New York (1989). ).
Vhodné samolepivé akryláty jsou komerčně dostupné.Suitable self-adhesive acrylates are commercially available.
Transdermální terapeutický systém podle vynálezu může přídavně obsahovat α-tokoferol nebo deriváty α-tokoferolu a/nebo činidlo zvyšující viskozitu, jako je hydroxypropylcelulóza.The transdermal therapeutic system of the invention may additionally comprise α-tocopherol or α-tocopherol derivatives and / or a viscosity enhancing agent such as hydroxypropylcellulose.
Vynález bude dále podrobněji znázorněn obrázkem a příkladem.The invention will now be illustrated in more detail by way of illustration and example.
Přehled obrázku na výkreseOverview of the figure in the drawing
Podle obrázku 1 obsahuje transdermální terapeutický systém podle vynálezu nosnou folii (podkladová folie) 1, která může mít nepatrně konvexní tvar, a která společně s membránou 3 tvoří zásobník 2, přičemž membrána 3 nereguluje uvolňování účinné složky. Na membránu 3 je nanesena podle obrázku 1 adhezní vrstva 5, která reguluje uvolňování účinné látky. Adhezní vrstva 5 je dále překryta krycí folií (odlepovací pásek) 3, která se před aplikací odstraní. Podle obrázku 1 může být nosná folie 1 opatřena prstencovým lemem 4, který leží na obvodové okrajové oblasti adhezní vrstvy 5 a je nalepen v místě dotyku na membránu 3.According to Figure 1, the transdermal therapeutic system according to the invention comprises a carrier film (backing film) 1 which may have a slightly convex shape and which together with the membrane 3 forms a reservoir 2, the membrane 3 not regulating the release of the active ingredient. An adhesive layer 5, which regulates the release of the active substance, is applied to the membrane 3 according to FIG. The adhesive layer 5 is further covered with a cover film (peel-off strip) 3, which is removed before application. According to Figure 1, the carrier film 1 may be provided with an annular rim 4, which lies on the peripheral edge area of the adhesive layer 5 and is glued at the point of contact with the membrane 3.
Příklad provedeníExemplary embodiment
Jako adhezní vrstva se použije samolepicí lepidlo na bázi silikonu (trimethylovaný silikon-dioxid, který byl zpracován s polydimethylsiloxanem majícím koncové trimethylsiloxyskupiny; tloušťka vrstvy za sucha je přibližně od 35 do 45 μην, hmotnost na jednotku specifického povrchu je přibližně od 50 do 60 g/m^). Krycí folie z PET (tloušťka přibližně 75 μην, hmotnost na jednotku specifického povrchu je přibližně 100 g/nrč) je pokryta pomocí potahovacího zařízení silikonovým lepidlem. Mikroporezní polyethylenová membrána nebo mikroporezní polypropylenová membrána (teplem svařovatelná; tloušťka přibližně 50 pm; hmotnost na jednotku specifického povrchu je přibližně 10 • · · ·· · • · · · · · · • · · 9 · · ·· · ······ • · · · • · ······· · · * g/m2) se potom laminuje na povlečenou krycí folii za vzniku laminátu z krycí folie, lepidla a membrány. Laminát se potom přivaří na nosnou folii z polyesteru (aluminizovaná s polyolefinovou lepící vrstvou (teplem svařovatelná); tloušťka přibližně 70 pm) pomocí svařovacího zařízení (se svařovacím prstencem) takovým způsobem, že pro zavedení účinné látky zůstane mezera. Plnitelný transdermální terapeutický systém (prázdný TTS) se naplní, například použitím Hamiltonovy injekční stříkačky nebo trubkového čerpadla vybaveného kanylou, následujícím roztokem účinné složky:The adhesive layer is a silicone-based adhesive (trimethylated silicone dioxide which has been treated with polydimethylsiloxane having trimethylsiloxy groups; the dry layer thickness is from about 35 to 45 μην, the weight per unit specific surface area is from about 50 to 60 g / m ^). The PET foil cover (thickness approx. 75 μην, weight per unit specific surface area is approx. 100 g / m2) is covered with a silicone adhesive coating device. Microporous polyethylene membrane or microporous polypropylene membrane (heat-sealable; thickness approx. 50 µm; weight per unit specific surface area is approx. 10 ° C) · 9 · · · · · ···· G / m 2 ) is then laminated to the coated topsheet to form a topsheet, adhesive, and membrane laminate. The laminate is then welded onto a polyester backing sheet (aluminized with a polyolefin adhesive layer (heat-sealable); approximately 70 µm thick) by means of a welding device (with a welding ring) in such a way that a gap remains for introducing the active agent. The refillable transdermal therapeutic system (empty TTS) is filled, for example using a Hamilton syringe or cannula tube pump, with the following active ingredient solution:
Složení roztoku účinné složky pro TTS:Composition of active ingredient solution for TTS:
mg/TTSmg / TTS
Po naplnění se mezera pro plnění zavaří. Naplněné transdermální terapeutické systémy se vyrážejí pomocí trnu.After filling, the filling gap is sealed. Filled transdermal therapeutic systems are punched using a mandrel.
Claims (8)
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| DE19517145A DE19517145C2 (en) | 1995-05-10 | 1995-05-10 | Transdermal therapeutic system (TTS) for administration of testosterone |
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| CZ287678B6 CZ287678B6 (en) | 2001-01-17 |
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| JP (1) | JPH11504643A (en) |
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| AU1429697A (en) * | 1995-12-29 | 1997-07-28 | Cygnus, Inc. | Systems and methods for the transdermal administration of androgenic agents |
| ATE226816T1 (en) * | 1996-07-03 | 2002-11-15 | Alza Corp | DEVICES FOR DRUG DELIVERY AND PRODUCTION METHOD |
| US6007837A (en) * | 1996-07-03 | 1999-12-28 | Alza Corporation | Drug delivery devices and process of manufacture |
| DE19646050A1 (en) * | 1996-11-08 | 1998-05-14 | Labtec Gmbh | Transdermal therapeutic system e.g. containing testosterone, melatonin |
| US6174545B1 (en) | 1997-07-01 | 2001-01-16 | Alza Corporation | Drug delivery devices and process of manufacture |
| WO1999061007A1 (en) * | 1998-05-22 | 1999-12-02 | Novosis Pharma Ag | Timed-release transdermal systems containing an active ingredient |
| FR2793689B1 (en) * | 1999-05-19 | 2001-08-24 | Pf Medicament | TRANSDERMAL DEVICE FOR THE ADMINISTRATION OF TESTOSTERONE OR A DERIVATIVE THEREOF |
| US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
| EP1611882B1 (en) | 2004-06-01 | 2010-04-07 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive patch |
| ZA200803087B (en) | 2005-10-12 | 2009-11-25 | Unimed Pharmaceuticals Llc | Improved testosterone gel and method of use |
| FR2895679B1 (en) * | 2005-12-29 | 2012-06-08 | Pf Medicament | STABILIZATION OF TESTOSTERONE IN TRANSDERMAL DEVICES |
| CN101480399B (en) * | 2008-09-25 | 2011-10-05 | 宋博 | Application of andrusol in preparing medicament for treating asthenospermia |
| DE102011012712A1 (en) | 2011-03-01 | 2012-09-06 | Frank Lehmann-Horn | Use of aldosterone receptor antagonists for the treatment of female sexual dysfunction |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4286592A (en) * | 1980-02-04 | 1981-09-01 | Alza Corporation | Therapeutic system for administering drugs to the skin |
| US4704282A (en) * | 1984-06-29 | 1987-11-03 | Alza Corporation | Transdermal therapeutic system having improved delivery characteristics |
| US4725439A (en) * | 1984-06-29 | 1988-02-16 | Alza Corporation | Transdermal drug delivery device |
| US4849224A (en) * | 1987-11-12 | 1989-07-18 | Theratech Inc. | Device for administering an active agent to the skin or mucosa |
| GB8804164D0 (en) * | 1988-02-23 | 1988-03-23 | Tucker J M | Bandage for administering physiologically active compound |
| US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US5152997A (en) * | 1990-12-11 | 1992-10-06 | Theratech, Inc. | Method and device for transdermally administering testosterone across nonscrotal skin at therapeutically effective levels |
| PT100502A (en) * | 1991-05-20 | 1993-08-31 | Alza Corp | PHARMACEUTICAL COMPOSITIONS FOR INCREASING THE CAPACITY OF PERMEACAO IN THE SKIN USING GLYCEROL MONOLINOLEATE |
| CA2075517C (en) * | 1992-04-01 | 1997-03-11 | John Wick | Transdermal patch incorporating a polymer film incorporated with an active agent |
| ATE184473T1 (en) * | 1992-06-11 | 1999-10-15 | Theratech Inc | USE OF GLYCERINE TO ATTENUATE TRANSDERMAL DRUG ADMINISTRATION |
| CA2161004C (en) * | 1993-04-20 | 2004-10-26 | Wilfried Fischer | Active ingredient patch |
| DE4313402A1 (en) * | 1993-04-23 | 1994-10-27 | Hexal Pharma Gmbh | Transdermal preparation of active compound |
| US5460820B1 (en) * | 1993-08-03 | 1999-08-03 | Theratech Inc | Method for providing testosterone and optionally estrogen replacement therapy to women |
-
1995
- 1995-05-10 DE DE19517145A patent/DE19517145C2/en not_active Expired - Fee Related
-
1996
- 1996-05-10 CZ CZ19973512A patent/CZ287678B6/en not_active IP Right Cessation
- 1996-05-10 HU HU9801130A patent/HUP9801130A3/en unknown
- 1996-05-10 DE DE59608150T patent/DE59608150D1/en not_active Expired - Fee Related
- 1996-05-10 ZA ZA963743A patent/ZA963743B/en unknown
- 1996-05-10 BR BR9608255A patent/BR9608255A/en not_active Application Discontinuation
- 1996-05-10 CA CA002220358A patent/CA2220358A1/en not_active Abandoned
- 1996-05-10 CN CN96193748A patent/CN1183723A/en active Pending
- 1996-05-10 PL PL96323145A patent/PL323145A1/en unknown
- 1996-05-10 AT AT96919765T patent/ATE208200T1/en not_active IP Right Cessation
- 1996-05-10 DK DK96919765T patent/DK0825865T3/en active
- 1996-05-10 AU AU58050/96A patent/AU702710B2/en not_active Ceased
- 1996-05-10 WO PCT/EP1996/002013 patent/WO1996035427A1/en active IP Right Grant
- 1996-05-10 NZ NZ308516A patent/NZ308516A/en unknown
- 1996-05-10 EP EP96919765A patent/EP0825865B1/en not_active Expired - Lifetime
- 1996-05-10 JP JP8533786A patent/JPH11504643A/en active Pending
- 1996-05-10 SK SK1497-97A patent/SK149797A3/en unknown
-
1997
- 1997-11-07 NO NO975140A patent/NO975140L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0825865B1 (en) | 2001-11-07 |
| AU5805096A (en) | 1996-11-29 |
| NZ308516A (en) | 1999-05-28 |
| PL323145A1 (en) | 1998-03-16 |
| HUP9801130A2 (en) | 1998-08-28 |
| HUP9801130A3 (en) | 2001-03-28 |
| WO1996035427A1 (en) | 1996-11-14 |
| CN1183723A (en) | 1998-06-03 |
| AU702710B2 (en) | 1999-03-04 |
| JPH11504643A (en) | 1999-04-27 |
| ZA963743B (en) | 1996-11-18 |
| CZ287678B6 (en) | 2001-01-17 |
| DK0825865T3 (en) | 2002-02-18 |
| DE19517145C2 (en) | 2000-02-24 |
| BR9608255A (en) | 1999-02-02 |
| SK149797A3 (en) | 1998-05-06 |
| EP0825865A1 (en) | 1998-03-04 |
| NO975140L (en) | 1997-11-10 |
| ATE208200T1 (en) | 2001-11-15 |
| DE59608150D1 (en) | 2001-12-13 |
| DE19517145C1 (en) | 1996-11-28 |
| CA2220358A1 (en) | 1996-11-14 |
| NO975140D0 (en) | 1997-11-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PD00 | Pending as of 2000-06-30 in czech republic | ||
| MM4A | Patent lapsed due to non-payment of fee |
Effective date: 19960510 |